Compositions comprising (R)-2-amino-3-phenylpropyl carbamate and uses thereof

ABSTRACT

The present invention relates to a newly identified solvate form of (R)-2-amino-3-phenylpropyl carbamate (APC) hydrochloride, a method of preparing APC hydrochloride, and methods of using the same to treat disorders. The invention further relates to methods of producing APC hydrochloride with increased purity.

STATEMENT OF PRIORITY

This application is a continuation of U.S. Pat. Application No.17/091,222, filed Nov. 6, 2020, now allowed, which is a continuation ofU.S. Pat. Application No. 16/331,069, filed Mar. 6, 2019, now U.S. Pat.No. 10,829,443, which is a 35 U.S.C. § 371 national phase application ofPCT Application PCT/US2017/050233, filed Sep. 6, 2017, which claims thebenefit, under 35 U.S.C. § 119(e), of U.S. Provisional Application No.62/383,822, filed Sep. 6, 2016; the entire contents of each of which areincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to a newly identified solvate form of(R)-2-amino-3-phenylpropyl carbamate (APC) hydrochloride, a method ofpreparing APC hydrochloride, and methods of using the same to treatdisorders. The invention further relates to methods of producing APChydrochloride with increased purity.

BACKGROUND OF THE INVENTION

APC is a phenylalanine analog that has been demonstrated to be useful inthe treatment of a variety of disorders, including excessive daytimesleepiness, cataplexy, narcolepsy, fatigue, depression, bipolardisorder, fibromyalgia, and others. See, for example, U.S. Pat. Nos.8,232,315; 8,440,715; 8,552,060; 8,623,913; 8,729,120; 8,741,950;8,895,609; 8,927,602; 9,226,910; and 9,359,290; and U.S. PublicationNos. 2012/0004300 and 2015/0018414. Methods for producing APC (whichalso has other names) and related compounds can be found in U.S. Pat.Nos. 5,955,499; 5,705,640; 6,140,532 and 5,756,817. All of the abovepatents and applications are hereby incorporated herein by reference intheir entireties for all purposes.

The present invention overcomes shortcomings in the art by providing anew solvate form of APC and a method of preparing APC with minimalcontaminants.

SUMMARY OF THE INVENTION

The present invention relates to the identification of a novel solvateform of APC which is a hemihydrate form. The invention further relatesto a method of preparing APC with minimal contaminants. The inventionadditionally relates to the use of the new solvate form and/or the APCwith increased purity for the treatment of disorders responsive to APC.

Accordingly, the invention relates to a solvate form of APChydrochloride characterized by a powder x-ray diffraction patternsubstantially the same as that shown in FIG. 1 and/or a powder x-raydiffraction pattern having peaks at about 7.0, 13.6, 16.2, 17.4, 17.8,18.5, 21.0, 21.7, 22.7, 23.0, 24.0, and 27.3 ± 0.2 °2θ.

The invention further relates to a process of preparing a solvate formof APC hydrochloride, comprising slurrying APC hydrochloride inacetonitrile/water (95%/5% v/v) and collecting the solvate by vacuumfiltration.

The invention further relates to a composition comprising APC, whereinless than about 10% of the APC in the composition is the solvate form ofthe invention.

The invention also relates to a composition comprising APC, wherein atleast about 30% of the APC in the composition is the solvate form of theinvention.

The invention additionally relates to a method of treating a disorderamenable to treatment with APC, e.g., narcolepsy, cataplexy, excessivedaytime sleepiness, drug addiction, sexual dysfunction, fatigue,fibromyalgia, attention deficit/hyperactivity disorder, restless legssyndrome, depression, bipolar disorder, or obesity in a subject in needthereof, or promoting smoking cessation in a subject in need thereof,comprising administering to the subject a dosage form comprising thesolvate form of the invention.

The invention also relates to a method of preparing APC hydrochloridewhile minimizing contamination with 2-chloropropane, the methodcomprising crystallizing APC in the presence of aqueous HCl, therebyproducing crystals of APC hydrochloride.

The invention further relates to a composition comprising APC withincreased purity as prepared by the method of the invention.

The invention additionally relates to a method of treating a disorderamenable to treatment with APC, e.g., narcolepsy, cataplexy, excessivedaytime sleepiness, drug addiction, sexual dysfunction, fatigue,fibromyalgia, attention deficit/hyperactivity disorder, restless legssyndrome, depression, bipolar disorder, or obesity in a subject in needthereof, or promoting smoking cessation in a subject in need thereof,comprising administering to the subject a dosage form comprising APCwith increased purity as prepared by the method of the invention.

The present invention is explained in greater detail in the drawingsherein and the specification set forth below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray pattern diffraction (XRPD) of crystalline formsof APC.

FIG. 2 shows the differential scanning calorimetry (DSC) thermogram ofhemihydrate Form B of APC.

FIG. 3 shows a comparison of the DSC thermograms of Forms A and B ofAPC.

FIG. 4 shows a comparison of the thermogravimetric (TG) thermograms ofForms A and B of APC.

FIG. 5 shows XRPD patterns of the conversion of Form A to Form B of APC.

DETAILED DESCRIPTION OF THE INVENTION

The present invention can be embodied in different forms and should notbe construed as limited to the embodiments set forth herein. Rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey the scope of the invention to thoseskilled in the art. For example, features illustrated with respect toone embodiment can be incorporated into other embodiments, and featuresillustrated with respect to a particular embodiment can be deleted fromthat embodiment. In addition, numerous variations and additions to theembodiments suggested herein will be apparent to those skilled in theart in light of the instant disclosure, which do not depart from theinstant invention.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. The terminology used in thedescription of the invention herein is for the purpose of describingparticular embodiments only and is not intended to be limiting of theinvention.

Unless the context indicates otherwise, it is specifically intended thatthe various features of the invention described herein can be used inany combination.

Moreover, the present invention also contemplates that in someembodiments of the invention, any feature or combination of features setforth herein can be excluded or omitted.

To illustrate, if the specification states that a complex comprisescomponents A, B and C, it is specifically intended that any of A, B orC, or a combination thereof, can be omitted and disclaimed singularly orin any combination.

All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference herein in their entiretyfor all purposes.

As used herein, “a,” “an,” or “the” can mean one or more than one. Forexample, “a” cell can mean a single cell or a multiplicity of cells.

Also as used herein, “and/or” refers to and encompasses any and allpossible combinations of one or more of the associated listed items, aswell as the lack of combinations when interpreted in the alternative(“or”).

Furthermore, the term “about,” as used herein when referring to ameasurable value such as an amount of a compound or agent of thisinvention, dose, time, temperature, and the like, is meant to encompassvariations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specifiedamount.

The term “consists essentially of” (and grammatical variants), asapplied to the compositions of this invention, means the composition cancontain additional components as long as the additional components donot materially alter the composition. The term “materially altered,” asapplied to a composition, refers to an increase or decrease in thetherapeutic effectiveness of the composition of at least about 20% ormore as compared to the effectiveness of a composition consisting of therecited components.

The term “therapeutically effective amount” or “effective amount,” asused herein, refers to the amount of a composition, compound, or agentof this invention that imparts a modulating effect, which, for example,can be a beneficial effect, to a subject afflicted with a disorder,disease or illness, including improvement in the condition of thesubject (e.g., in one or more symptoms), delay or reduction in theprogression of the condition, delay of the onset of the disorder, and/orchange in clinical parameters, disease or illness, etc., as would bewell known in the art. For example, a therapeutically effective amountor effective amount can refer to the amount of a composition, compound,or agent that improves a condition in a subject by at least 5%, e.g., atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, or at least 100%.

“Treat” or “treating” or “treatment” refers to any type of action thatimparts a modulating effect, which, for example, can be a beneficialeffect, to a subject afflicted with a disorder, disease or illness,including improvement in the condition of the subject (e.g., in one ormore symptoms), delay or reduction in the progression of the condition,and/or change in clinical parameters, disease or illness, etc., as wouldbe well known in the art.

A “disorder amenable to treatment with APC” refers to any disorder inwhich administration of APC to a subject results in the treatment of oneor more symptoms of the disorder in the subject. Examples of suchdisorders include, without limitation, narcolepsy, cataplexy, excessivedaytime sleepiness, drug addiction, sexual dysfunction, fatigue,fibromyalgia, attention deficit/hyperactivity disorder, restless legssyndrome, depression, bipolar disorder, or obesity.

“Pharmaceutically acceptable,” as used herein, means a material that isnot biologically or otherwise undesirable, i.e., the material can beadministered to an individual along with the compositions of thisinvention, without causing substantial deleterious biological effects orinteracting in a deleterious manner with any of the other components ofthe composition in which it is contained. The material would naturallybe selected to minimize any degradation of the active ingredient and tominimize any adverse side effects in the subject, as would be well knownto one of skill in the art (see, e.g., Remington’s PharmaceuticalScience; 21^(st) ed. 2005).

“Concurrently” means sufficiently close in time to produce a combinedeffect (that is, concurrently can be simultaneously, or it can be two ormore events occurring within a short time period before or after eachother). In some embodiments, the administration of two or more compounds“concurrently” means that the two compounds are administered closelyenough in time that the presence of one alters the biological effects ofthe other. The two compounds can be administered in the same ordifferent formulations or sequentially. Concurrent administration can becarried out by mixing the compounds prior to administration, or byadministering the compounds in two different formulations, for example,at the same point in time but at different anatomic sites or usingdifferent routes of administration.

The present invention relates to the identification and characterizationof a new solvate form of APC hydrochloride, called Form B. The solvateform is a hemihydrate form and is the more stable form of the compoundat higher humidity levels compared to the anhydrous Form A.

The structure of APC free base is given below as formula I.

Thus, one aspect of the invention relates to a solvate form of APChydrochloride characterized by a powder x-ray diffraction patternsubstantially the same as that shown in FIG. 1 for solvate Form B and/ora powder x-ray diffraction pattern having peaks at about 7.0, 13.6,16.2, 17.4, 17.8, 18.5, 21.0, 21.7, 22.7, 23.0, 24.0, and 27.3 ± 0.2°2θ. In some embodiments, the solvate is further characterized bydifferential scanning calorimetry as having a broad endotherm with onsetat 69.1° C. and peak at 71.7° C. and a sharp endotherm with onset at182.5° C. and peak at 183.6° C. In some embodiments, the solvate isfurther characterized by having a solubility in buffer solution of about700-750 mg/ml at pH 1-6.5. In certain embodiments, the solvate form is ahemihydrate.

In some embodiments, the solvate form is further characterized as beingproduced by slurrying APC in acetonitrile/water (95%/5% v/v).

As used herein, the term “hemihydrate,” refers to a hydrate in which onemolecule of water is associated with two molecules of APC.

As used herein, the term “crystalline” refers to a material thatcontains a specific compound, which may be hydrated and/or solvated, andhas sufficient crystal content to exhibit a discernible diffractionpattern by XRPD or other diffraction techniques.

The solvate form may be prepared by a method comprising slurrying APChydrochloride in a suitable solvent system (e.g., acetonitrile/water(95%/5% v/v)) and collecting the solvate crystals using a suitabletechnique, e.g., vacuum filtration. In some embodiments, the process iscarried out at about room temperature, e.g., about 20° C. to about 28°C. and in about 5-15 (e.g., 10) volumes of solvent. In some embodiments,the slurrying step is carried out for a sufficient length of time forthe solvate to form, e.g., at least about 10 hours, e.g., at least about10, 15, 20, 25, 50, 75, or 100 hours or more.

In some embodiments, the process is carried out at a temperature ofabout 20° C. and in about 5 volumes of solvent. In some embodiments, theslurrying step is carried out for a sufficient length of time for thesolvate to form, e.g., about 1-2 hours.

The wet Form B prepared by the methods described herein may be dried byany method suitable for maintaining Form B and limiting dehydration toForm A. In some embodiments, the drying is carried out at a temperatureof about 20° C. to about 25° C. In some embodiments, the drying iscarried out at reduced pressure, e.g., about 600-950 mbar e.g., about700-750 mbar. In some embodiments, the drying is carried out for asuitable length of time to achieve complete dryness, e.g., about 4-40hours, e.g., about 10-24 hours. In some embodiments, the drying iscarried out at high humidity, e.g., about 80-100% relative humidity.

Another aspect of the invention relates to a composition, e.g., a dosageform, comprising APC, wherein less than about 10% of the APC in thecomposition is solvate Form B. In some embodiments, less than about 9%,8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the APC is in solvate Form B. Insome embodiments, the dosage form is an oral dosage form, e.g., a tabletor a capsule, including, e.g., an immediate release dosage form.

A further aspect of the invention relates to a composition, e.g., adosage form, comprising APC, wherein at least about 30% of the APC inthe composition is solvate Form B, e.g., about 30% to about 99% or more.In some embodiments, at least about 40%, 50%, 60%, 70%, 80%, or 90% ofthe APC is solvate Form B. In some embodiments, the dosage form is anoral dosage form, e.g., a tablet or a capsule, including, e.g., animmediate release dosage form.

In some embodiments, the dosage form is an immediate release dosage formthat releases at least 85%, e.g., at least 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, of the APC HCl containedtherein within a period of less than 15 minutes after administration ofthe tablet to a subject. Such immediate release dosage forms aredisclosed, for example, U.S. Provisional Application No. 62/383,818,incorporated herein by reference in its entirety.

Formulations of APC, including immediate release formulations, may beprocessed into unit dosage forms suitable for oral administration, suchas for example, filled capsules, compressed tablets or caplets, or otherdosage form suitable for oral administration using conventionaltechniques. Immediate release dosage forms prepared as described may beadapted for oral administration, so as to attain and maintain atherapeutic level of APC over a preselected interval. In certainembodiments, an immediate release dosage form as described herein maycomprise a solid oral dosage form of any desired shape and sizeincluding round, oval, oblong cylindrical, or polygonal. In one suchembodiment, the surfaces of the immediate release dosage form may beflat, round, concave, or convex.

In particular, when the immediate release formulations are prepared as atablet, the immediate release tablets contain a relatively largepercentage and absolute amount of APC and so are expected to improvepatient compliance and convenience by replacing the need to ingest largeamounts of liquids or liquid/solid suspensions. One or more immediaterelease tablets as described herein can be administered, by oralingestion, e.g., closely spaced, in order to provide a therapeuticallyeffective dose of APC to the subject in a relatively short period oftime.

Where desired or necessary, the outer surface of an immediate releasedosage form may be coated, e.g., with a color coat or with a moisturebarrier layer using materials and methods known in the art.

The dosage form may contain any amount of APC or a pharmaceuticallyacceptable salt thereof suitable for administration as a unit dosageform. In some embodiments, the dosage form contains about 1 mg to about1000 mg of the drug or any range or value therein, e.g., about 10 mg toabout 500 mg, e.g., about 37.5 mg, about 75 mg, about 150 mg, or about300 mg.

APC or a pharmaceutically acceptable salt thereof may be obtained orsynthesized by methods known in the art and as described herein. Detailsof reaction schemes for synthesizing APC have been described in U.S.Pat. Nos. 5,705,640; 5,756,817; 5,955,499; and 6,140,532, allincorporated herein by reference in their entirety.

During the development of manufacturing processes for APC, it was foundthat unacceptable levels of the impurity 2-chloropropane (i.e.,isopropyl chloride) could appear during the crystallization of APChydrochloride. It is desirable to minimize 2-chloropropane as it is apotential genotoxic impurity. Thus, one aspect of the invention relatesto an improved method of preparing APC hydrochloride in whichcontamination with 2-chloropropane is minimized. With this improvedmethod, the level of 2-chloropropane in the final product may be lessthan about 10 ppm, e.g., less than about 9, 8, 7, 6, 5, 4, 3, 2, or 1ppm.

Thus, one aspect of the invention relates to a method of preparing APChydrochloride while minimizing contamination with 2-chloropropane, themethod comprising crystallizing APC in the presence of aqueous HCl,thereby producing crystals of APC hydrochloride. The crystallization maybe carried out with the free base of APC in a suitable solvent, e.g.,isopropanol.

In some embodiments, the aqueous HCl is 37% aqueous HCl. In someembodiments, the crystallization is carried out at a temperature ofabout 15° C. to about 40° C., e.g., about 25° C. to about 35° C.,followed by cooling to a temperature of less than 0° C., e.g., about -5°C. to about -25° C., e.g., about -15° C. In some embodiments, thecrystals are dried at a temperature less than about 45° C., e.g., lessthan about 40° C., 35° C., or 30° C. In some embodiments, thecrystallization is carried out in the presence of about 1 to about 1.2molar equivalents (e.g., about 1.05 molar equivalents) of 37% aqueousHCl at a temperature of about 25° C. to about 35° C. followed by atemperature of about -15° C.

Methods are disclosed herein to treat conditions amenable to treatmentby APC, by administering an effective amount of one or more dosage formsas described herein. For example, the present dosage forms can beadministered to treat a subject in need of treatment for narcolepsy,cataplexy, excessive daytime sleepiness, drug addiction, sexualdysfunction, fatigue, fibromyalgia, attention deficit/hyperactivitydisorder, restless legs syndrome, depression, bipolar disorder, orobesity, or to promoting smoking cessation in a subject in need thereof.See, e.g., U.S. Pat. Nos. 8,232,315; 8,440,715; 8,552,060; 8,623,913;8,729,120; 8,741,950; 8,895,609; 8,927,602; 9,226,910; and 9,359,290;and U.S. Publication Nos. 2012/0004300 and 2015/0018414; each of whichis incorporated by reference in its entirety with respect to thedisorder to be treated.

The dosage forms disclosed herein can also be provided as a kitcomprising, for example, a container comprising a plurality of immediaterelease tablets or capsules, which tablets or capsules can beindividually packaged, as in foil envelopes or in a blister pack. Thetablets or capsules can be packaged in many conformations with orwithout desiccants or other materials to prevent ingress of water.Instruction materials or means, such as printed labeling, can also beincluded for their administration, e.g., sequentially over a preselectedtime period and/or at preselected intervals, to yield the desired levelsof APC in vivo for preselected periods of time, to treat a preselectedcondition.

A daily dose of about 1 to about 2000 mg of APC or a pharmaceuticallyacceptable salt thereof may be administered to accomplish thetherapeutic results disclosed herein. For example, a daily dosage ofabout 10-1000 mg, e.g., about 20-500 mg, in single or divided doses, isadministered. In some embodiments, the daily dose may be about 0.01 toabout 150 mg/kg body weight, e.g., about 0.2 to about 18 mg/kg bodyweight.

In one embodiment of the invention, APC is administered to the subjectas needed to treat a disorder. The compound can be administeredcontinuously or intermittently. In one embodiment, the compound isadministered to the subject more than once a day, e.g., 2, 3, or 4 timesper day, or once every 1, 2, 3, 4, 5, 6, or 7 days. In anotherembodiment, the compound is administered to the subject no more thanonce a week, e.g., no more than once every two weeks, once a month, onceevery two months, once every three months, once every four months, onceevery five months, once every six months, or longer. In a furtherembodiment, the compound is administered using two or more differentschedules, e.g., more frequently initially (for example to build up to acertain level, e.g., once a day or more) and then less frequently (e.g.,once a week or less). In other embodiments, the compound can beadministered by any discontinuous administration regimen. In oneexample, the compound can be administered not more than once every threedays, every four days, every five days, every six days, every sevendays, every eight days, every nine days, or every ten days, or longer.The administration can continue for one, two, three, or four weeks orone, two, or three months, or longer. Optionally, after a period ofrest, the compound can be administered under the same or a differentschedule. The period of rest can be one, two, three, or four weeks, orlonger, according to the pharmacodynamic effects of the compound on thesubject. In another embodiment, the compound can be administered tobuild up to a certain level, then maintained at a constant level andthen a tailing dosage.

In one aspect of the invention, APC is delivered to a subjectconcurrently with an additional therapeutic agent. The additionaltherapeutic agent can be delivered in the same composition as thecompound or in a separate composition. The additional therapeutic agentcan be delivered to the subject on a different schedule or by adifferent route as compared to the compound. The additional therapeuticagent can be any agent that provides a benefit to the subject. Furtheragents include, without limitation, stimulants, anti-psychotics,antidepressants, agents for neurological disorders, and chemotherapeuticagents. One therapeutic agent that can be administered during the sameperiod is Xyrem®, sold commercially by Jazz Pharmaceuticals, which isused to treat narcolepsy and cataplexy. See U.S. Patent Nos. 8,952,062and 9,050,302.

The present invention finds use in research as well as veterinary andmedical applications. Suitable subjects are generally mammaliansubjects. The term “mammal” as used herein includes, but is not limitedto, humans, non-human primates, cattle, sheep, goats, pigs, horses,cats, dog, rabbits, rodents (e.g., rats or mice), etc. Human subjectsinclude neonates, infants, juveniles, adults and geriatric subjects.

In particular embodiments, the subject is a human subject that has adisorder amenable to treatment with APC. In other embodiments, thesubject used in the methods of the invention is an animal model of adisorder amenable to treatment with APC.

The subject can be a subject “in need of” the methods of the presentinvention, e.g., in need of the therapeutic effects of the inventivemethods. For example, the subject can be a subject that is experiencinga disorder amenable to treatment with APC, is suspected of having adisorder amenable to treatment with APC, and/or is anticipated toexperience a disorder amenable to treatment with APC, and the methodsand compositions of the invention are used for therapeutic and/orprophylactic treatment.

The present invention is explained in greater detail in the followingnon-limiting Examples.

Example 1 Solvate Form of (R)-2-amino-3-phenylpropyl CarbamateHydrochloride

A polymorph and solvate screen of APC was conducted to evaluate itspropensity to exist in various solid forms and determine the stable formof the compound. Four lots of APC were partially characterized. All lotswere found to be the same anhydrous, crystalline material, and thematerial was designated Form A.

The polymorph and solvate screen of APC was conducted using differentcrystallization techniques to vary conditions of nucleation and growthinvestigating both thermodynamic and kinetic conditions. Solvent systemswith varying chemical properties were used, and selected experimentsfocused specifically on process solvents. Selected experiments were alsoconducted via salt formation experiments using the free base andtargeting the monohydrochloride salt.

A crystalline hemihydrate form was identified and named Form B. Form Bwas prepared from a slurry in acetonitrile:water (95%:5% v:v) at roomtemperature. Form B was also produced from a slurry in p-dioxane:water(95%:5% v:v) at subambient temperature. Form B was also observed asmixtures with Form A or other crystalline materials from variousexperiments such as evaporations and crash precipitations in ethanol,hexafluoroisopropanol, methanol, and/or water. Partial conversion toForm B was also observed after stressing of Form A at approximately 75%humidity (RH).

The XRPD pattern of Form B is shown in FIG. 1 . The differentialscanning calorimetry (DSC) thermogram of Form B exhibited a broadendotherm at 69.1° C. (onset), 71.7° C. (peak max) (FIG. 2 ). Theendotherm is associated with a corresponding weight loss of 3.5% on theTG thermogram, which calculates to approximately 0.5 moles of water.These events are likely due to dehydration. A sharp endotherm isobserved at 182.5° C. (onset), 183.6° C. (peak max) followed by anexotherm at 185.2° C. (peak max) possibly due to a recrystallizationevent. This was followed by an endotherm at 190.1° C. (peak max). DSCand thermogravimetry (TG) thermogram comparisons of Form B and Form Aare shown in FIG. 3 and FIG. 4 .

Karl Fischer analysis indicated Form B contained -3.71 wt% water orapproximately 0.5 moles. This data was consistent with the weight lossobserved in the TG thermogram.

Microscopy images were taken of Form B and showed elongated plates(~50-100 µm) and smaller fragments.

The aqueous solubility of Form B was measured at over 700 mg/ml indifferent pH buffers as shown in Table 1.

TABLE 1 Solvent pH (buffer) measured starting conditions pH (bufferedsample) Solubility (mg/ml mean of triplicates) Buffer solution pH 1.21.2 4.5 732.26 Buffer solution pH 4.5 4.5 5.7 733.04 Buffer solution pH5.5 5.5 6.0 741.79 Buffer solution pH 7.4 7.4 6.4 746.41

Crystals of APC were submitted for single crystal structure analysis.The structure was determined by single crystal X-ray diffraction. Themonoclinic cell parameters and calculated volume are: a = 15.9491(8) Å;b = 5.8431(6) Å; c = 12.7663(12) Å; β = 94.404(5)° (α = γ - 90°); V =1186.21(18) Å³. The formula weight of the asymmetric unit in the crystalstructure of APC Form B is 239.70 g mol⁻¹ with Z = 4, resulting in acalculated density of 1.342 g cm⁻³. The space group was determined to beC2 (no. 5). The space group and unit cell parameters are in agreementwith those obtained previously from XRPD indexing for Form B.

When adequate relative RH is achieved Form A converts to Form B.Interconversion slurry experiments conducted with Form A and Form Bsuggest that Form B is the more stable form at approximately 50% RH orgreater at room temperature.

Slurry experiments were performed with various water activities startingwith Form A only and also by conducting interconversion slurries orpre-saturating solutions with APC and then adding equal amounts of FormA and Form B. When slurrying Form A only, conversion to Form B at roomtemperature occurred at 67% RH, and 40% RH at 2-8° C. With theinterconversion slurries, Form B was isolated from all experiments withrelative humidities ranging from 50% to 70%.

Two small scale experiments were conducted in acetonitrile:water (95%:5%v:v) to evaluate whether an overnight conversion of Form A to Form B waspossible. Experiments were conducted at approximately 98 mg/ml andapproximately 51 mg/ml. Both experiments resulted in Form B afterslurrying for approximately 24 hours indicating that kinetics ofconversion of Form A to Form B can occur within 24 hours (FIG. 5 ).

Drying studies were performed on Form B. The drying experiments wereperformed under various temperatures with and without vacuum.Additionally, milling, storage under desiccant, and low RH stressingwere conducted. In all experiments, Form B partially or fully dehydratedto Form A. Partial conversion to Form A occurred after vacuum drying atambient temperature for 1 day, heating at 40° C. for 1 day, storageunder desiccant for 1 day, and stressing at 33% RH for 2 weeks. Fulldehydration to Form A occurred after vacuum drying at 50° C. for 1 day,heating at 80° C. for 1 day, and milling. The results of the dryingstudies of Form B suggest that Form B is not stable under low RH or atelevated temperature.

A scaled-up method for producing Form B was developed. APC was slurriedin acetonitrile:water (95%:5% v:v) while maintaining the temperature at22° C. Subsamples of the slurry were taken periodically, vacuumfiltered, and analyzed by XRPD. It was found that mixtures of Form Bwith trace amounts of Form A were observed from approximately 20 to 28.5hours. Compared to the subsample taken at 20 hours, an increase in FormA was observed in the subsample taken at 24 hours. This may be due todehydration caused by vacuum filtration and low atmospheric humidity.The slurry was stirred for an additional 3 days and another subsamplewas taken. XRPD analysis indicated that a subsample taken atapproximately 91 hours was Form B. The slurry was isolated by vacuumfiltration after slurrying of approximately 121.5 hours, and the wetcake was washed with two filter cake volumes of acetonitrile:water(95%:5% v:v). XRPD analysis indicated the wet cake was composed of FormB. The wet cake was dried under vacuum at ambient temperature forapproximately 16 hours. XRPD analysis indicated the dried materialdehydrated slightly to Form A, with approximately 5% Form A in themixture. The dehydration may be avoided by drying without vacuum ordrying under high RH (approximately 75%).

The mixture of Form B with a trace amount of Form A was additionallycharacterized by Karl Fischer for water content determination andsolution ¹H NMR for an estimation of solvent convent. Karl Fischeranalysis indicated the mixture contained approximately 3.52% water or0.47 moles of water per mole of APC. The ¹H NMR spectrum was consistentwith the structure of APC. Water and a trace amount of acetonitrile(0.003 moles per mole of APC) were also observed in the spectrum.

An additional scaled-up method for producing Form B was developed thatreduced reaction time and volume and increased yield. Isolation of FormB from Form A was carried out in 5 volumes of solvent(acetonitrile:water (95%:5% v:v)) at about 20° C. for about 1-2 hours.The drying process was carried out at an oven temperature of 20-25° C.and low vacuum (700-750 mbar). Under these drying conditions Form B wasstable and no detectable Form A was formed. This method was used on a4.5 kg batch of APC and produced Form B with a yield of 93.7%.

Example 2 Synthesis of (R)-2-amino-3-phenylpropyl CarbamateHydrochloride With Minimal 2-Chloropropane

Initially, large scale preparation of APC hydrochloride from the freebase was carried out as follows. APC free base solution in isopropylalcohol was diluted with isopropyl alcohol to a final concentration of19% w/w. Water (37 g/mol) was added, and the solution was heated to 70°C. Gaseous HCl (about 2 equivalents) was added in the headspace abovethe solution through a flow meter. As HCl dissolved the temperatureincreased to 75-80° C. The clear supersaturated solution was seededquickly within the 15 minutes following the addition. APC hydrochloridecrystallized. The suspension was stirred at 78° C., then cooled to 40°C. in 10 hours. The suspension was further cooled to 20° C., then to 3°C. in 2 hours, and stirred at this temperature for 1 hour. The solid wasrecovered by filtration and washed with isopropyl alcohol. The wet cakewas dried under reduced pressure for at least 16 hours.

This method produced unacceptable levels of the potential genotoxicimpurity 2-chloropropane (2-CP), which is preferentially at a level ofno more than 5 ppm. The levels were likely due to the harshcrystallization conditions (HCl charging close to the boiling point ofthe reaction mixture, stirring 1 hour at 78° C., then cooling to 40° C.in 10 hours, then progressively cooling to 3° C.). Drying the crystals,even at elevated temperatures, did not reduce the amount of 2-CP.Reslurrying the crystals also was ineffective.

Given the difficulty of removing 2-CP once it was formed, it wasnecessary to revise the crystallization conditions to avoid theformation of 2-CP. Starting with APC free base in isopropyl acetateprevented formation of 2-CP but the crystallization was poorlycontrolled, resulting in the formation of a thick crust in the reactor,and produced very small crystals, so the conditions were not suitable.Charging the HCl gas at a lower temperature (30-35° C.) controlledformation of 2-CP but the crystallization was poorly controlled,resulting in the formation of a thick crust in the reactor, and produceda less crystalline material, so the conditions were not suitable.

Because the charging of HCl in gas form caused unwanted spontaneouscrystallization in the conditions evaluated, adding HCl in the form of a37% aqueous solution was tested. This protocol increases the totalamount of water 1.76-fold from 37 g/mol to 65 g/mol so the resultingsuspension has to be cooled to a lower temperature to maximize theyield. However, the larger amount of water combined with the lower molarexcess of acid (1.05 molar equivalents compared to 2 molar equivalents)and the lower temperature contributes to minimizing the rate offormation of 2-CP.

The following general protocol was developed. APC free base solution inisopropyl alcohol was diluted with isopropyl alcohol to a finalconcentration of 19% w/w. The clear solution was warmed up to 25° C.(20-30° C.). 37% aqueous HCl was slowly added to the clear solution. Thetemperature was allowed to rise to 30° C. Seeding was applied soonafterwards (within 15 minute). The clear solution was stirred for 15minutes at 30° C., whereby APC hydrochloride slowly startedcrystallizing. 37% aqueous HCl was further added to the suspension. Themixture was stirred at 30° C. for 1 hour, then cooled to -15° C. in 2hours, and stirred at this temperature for 1 hour. The product wasrecovered as a white crystalline solid and washed with isopropylalcohol. The wet product was dried at 35° C. (30-40° C.) under anitrogen stream.

In one example, a solution of APC free base 16.9 g, 0.0871 mol) wasdiluted with isopropyl alcohol (43.8 g) and warmed to 30° C. 37% aqueousHCl (4.51 g, 0.0458 mol, 0.525 mol equiv) was added dropwise, keepingthe temperature ≤ 35° C. APC hydrochloride (22 mg) was added to theclear solution. The solution became turbid almost immediately. After 15minutes a suspension was obtained. No crystallization around the reactorwalls occurred. Further 37% aqueous HCl (4.51 g, 0.0458 mol, 0.525 molequiv) was added dropwise, keeping the temperature ≤ 35° C. Aftercharging the suspension was stirred at 30° C. for 1 hour, cooled to -15°C. in 2 hours and stirred 2 hours at this temperature. The product wasrecovered by filtration, washed with IPA (16.7 g) and dried at 35° C.,30-50 mbar for 17 hours under air flow. 16.87 g product was recovered(yield 83.96%). The crystallization occurred very smoothly. The productwas a white crystalline powder. No 2-CP was detected.

Two additional batches were prepared using the same protocol. In bothbatches 2-CP levels in the product were less than 1 ppm.

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein. Allpublications, patent applications, patents, patent publications, and anyother references cited herein are incorporated by reference in theirentireties for the teachings relevant to the sentence and/or paragraphin which the reference is presented.

1-15. (canceled)
 16. A method of preparing (R)-2-amino-3-phenylpropylcarbamate hydrochloride while minimizing contamination with2-chloropropane, the method comprising crystallizing(R)-2-amino-3-phenylpropyl carbamate from isopropanol in the presence ofaqueous HCl, thereby producing crystals of (R)-2-amino-3-phenylpropylcarbamate hydrochloride.
 17. The method of claim 16, wherein thecrystallizing is performed at a temperature of about 25° C. to about 30°C.
 18. The method of claim 16, further comprising drying the crystals of(R)-2-amino-3-phenylpropyl carbamate hydrochloride at a temperature ofabout 35° C. or less.
 19. The method of claim 16, wherein the amount of2-chloropropane in the (R)-2-amino-3-phenylpropyl carbamatehydrochloride is less than about 5 ppm.
 20. A composition comprising(R)-2-amino-3-phenylpropyl carbamate hydrochloride prepared by themethod of claim 16, the composition comprising less than about 5 ppm2-chloropropane.
 21. (canceled)
 22. The composition of claim 20, whereinthe composition is a dosage form.
 23. The composition of claim 22,wherein the composition is an immediate release oral dosage form. 24.The composition of claim 23, wherein the composition is a tablet or acapsule.
 25. A method of treating narcolepsy, cataplexy, excessivedaytime sleepiness, drug addiction, sexual dysfunction, fatigue,fibromyalgia, attention deficit/hyperactivity disorder, restless legssyndrome, depression, bipolar disorder, or obesity in a subject in needthereof, or promoting smoking cessation in a subject in need thereof,comprising administering to the subject the composition of claim
 20. 26.The method of claim 25, wherein the tablet is administered once per day.27. The method of claim 25, wherein the tablet is administered more thanonce per day.
 28. The method of claim 16, wherein the amount of2-chloropropane in the (R)-2-amino-3-phenylpropyl carbamatehydrochloride is less than about 1 ppm.
 29. The composition of claim 20wherein the amount of 2-chloropropane in the composition is less thanabout 1 ppm.